Novel prostaglandins

ABSTRACT

This disclosure describes novel 15-hydroxy prostanoic acid derivatives having anti-ulcer bronchodilator, and hypotensive activity.

United States Patent [1 1 Schaub et a].

[ May 20, 1975 NOVEL PROSTAGLANDINS [75] Inventors: Robert Eugene Schaub, Upper Saddle River; Martin Joseph Weiss, Oradell, both of NJ.

[73] Assignee: American Cyanamid Company,

Stamford, Conn.

[22] Filed: Apr. 20, 1973 [2l] Appl. No.: 353,152

[56] References Cited UNITED STATES PATENTS 3,725,454 4/1973 Beal 260/488 Caton 260/557 Pike 260/468 FOREIGN PATENTS OR APPLICATIONS 784,809 12/1972 Belgium 260/468 OTHER PUBLICATIONS Bundy, Annals N.Y., Academy of Science, 180, 79 (1971).

Primary ExaminerRobert Gerstl Attorney, Agent, or Firm-Edward A. Conroy, Jr.

[57] ABSTRACT This disclosure describes novel l5-hydroxy prostanoic acid derivatives having anti-ulcer bronchodilator, and hypotensive activity.

28 Claims, No Drawings NOVEL PROSTAGLANDINS BRIEF SUMMARY OF THE INVENTION This invention relates to novel IS-hydroxy prostanoic DETAILED DESCRIPTION OF THE INVENTION Also embraced within the scope of the present invenacids and derivatives, as well as to intermediates and tion are the non-toxic, pharmaceutically acceptable methods for their preparation. The novel prostanoic acids and derivatives of this invention may be represented by the following general formula:

salts of the novel compounds of the present invention when R is hydroxy. The cations comprised in these salts include, for example, the non-toxicmetal cations such as the sodium ion, potassium ion, calcium ion, and

0 l0 magnesium ion as well as the organic amine cations H such as the tri(lower alkyl)amine cations (e.g., triethyl- Y amine, tri(B-hydroxyethyl)amine, procaine and the like).

2 l R R 1 (CH (1 4\| The compounds of this invention include all possible n C C1s-(CH) -(CH -R optical isomers. The novel compounds of the present I invention are usually obtainable as oils having charac- OR2 teristic absorption spectra. They are relatively insoluble in water but are relatively soluble in common orwherein Y is a divalent radical selected from the group ganic solvents such as ethanol, ethyl acetate, dimethylconsisting of those of the formulae: formamide, and the like. The cationic salts of the compounds when R is hydroxy are, in general, white to yel- O HO ,H H low crystalline solids having characteristic melting ll 1 C and C 3 points and absorption spectra. They are relatively soluble in water, methanol, and ethanol but are relatively insoluble in benzene, diethyl ether and petroleum and Z is a divalent radical selected from the group conether. sisting of those of the formulae: The novel compoundsof the present invention may l a (cn (CH ClICH (CH -CH 4 -(CH OCH -(CH -SQH and H e i H wherein m is an integer from 3 to 8, inclusive, p is an 40 be readily prepared from certain cycloalkenone interinteger from 2 to 6 inclusive, R is an alkyl group having up to 3 carbon atoms, and R is an alkyl group having up to 3 carbon atoms, a fluorine atom or a phenyl group; the moiety C C is ethylene, or transvinylene; R, is selected from the group consisting of lower alkyl groups having up to 3 carbon atoms; R is selected from the group consisting of hydrogen, triphenylmethyl, and monoor di-methoxy substituted triphenylmethyl; R is hydroxyl or alkoxy having from one to twelve carbon atoms; R is selected from the group consisting of hydrogen and lower alkyl groups having up to 3 carbon atoms with the proviso that when R, is alkyl then R is hydrogen; n is an integer having the value one or two; s is zero or an integer having the value one to five inclusive; t is zero or one; and R is selected from the group consisting of cycloalkyl groups having from three to nine carbon atoms, cycloalkenyl groups having from five to nine carbon atoms, mono or dilower alkyl substituted cycloalkyl groups having from three to eight carbon atoms in the ring, mono or dilower alkyl substituted cycloalkenyl groups having from five to eight carbon atoms in the ring and adamantyl groups; with the proviso that only one double bond or cyclopropyl group can be immediately adjacent to C and with the additional proviso that when n is one, 7

Z is (C]-I and R is a saturated cycloalkyl or adamantyl group then the sum of s and t is at least one.

mediates some of which may be represented by the following general formula:

wherein Z and n are as defined above, and R has all the possibilities given above for R except that it is not hydroxyl. The preparation of certain of these cycloalkenones is described in Belgium Pat. No. 786,215 (granted and opened to inspection Jan. 15, 1973 Others of the requisite cycloalkenones are prepared by extension of the methods described therein.

The preparation of the cycloalkenone intermediates (X, XI) bearing a cis double bond in the carboxylic acid side chain can be accomplished by the sequences illustrated in Flowsheets A or B. In Flowsheet A which follows, n and p are as hereinabove defined.

F'LOWSHEET A continued 2. H H (CH I I CH2 (CH )pCOH o i F (CH2)n c c H CH2 (CH )p-COCH o In the above Flowsheet A, the sequence wherein a Z-carbalkoxycycloalkanone (I) is transformed to a 2- (,B-hydroxyethyl)cycloalk-Z-en-l-one (VII) is carried out in the manner described in Belgium Pat. No. 786,215 citered hereinabove. Methyl ether cleavage of the corresponding 2-(B-methoxyethyl)cycloalkenone is achieved by treating with boron tribromide. Oxidation of the alcohol with Collins reagent (chromium trioxidepyridine complex) in methylene chloride under anhydrous conditions provides the aldehyde (VIII),which is then treated in anhydrous dimethylsulfoxide with the ylid (IX) prepared from an (w-carboxyalkyl)triphenyl phosphonium bromide and sodium hydride. The use of dimethylsulfoxide as a solvent for this reaction leads to the predominant formation of the desired cis double bond in (X). The acid function in (X) can be esterified in the usual fashion; with diazomethane, the methyl ester (XI) is obtained.

Cyclopentenones such as (XVI) may also be prepared by the sequence illustrated in F lowsheet B, which follows and in which p is as hereinabove defined.

FLOW SHEET B X1 (XIII) cis I 5 1 ca c=c-(cH coon HO P 1(XIV) ids} CH2-C=C-(CH2) .COOH

H H I =8-(cH cooH (XVI) In Flowsheet B, above the bicyclic hemiacetal (XII) [P.A. Grieco, .Iourn. Org. Chem, 37, 2363 (1972)] is treated with ylid (XIII) to give the l-hydroxy-3- cyclopentene (XIV). Oxidation with Jones reagent gives the corresponding ketone (XV), which on base treatment furnishes the required cyclopentenone (XVI), which can then by esterified in the usual manner.

The 9-keto-l3-trans-prostenoic acids and esters of this invention may be prepared by the novel conjugate addition process outlined in the Flowsheet C which follows. In Flowsheets, C, R, R Z, R R7 n, s and t are as defined hereinabove; R is a lower alkyl group (each of the three R radicals bonded to an aluminum atom does not necessarily have to be the same), R' has all the possibilities given hereinabove for R except hydrogen, and R has all the possibilities given hereinabove for R except that it does not include cycloalkenyl, cyclopropyl or adamantyl groups.

(XVII) (XVIII) (XIX) Li H FLOWSHEET c Continued (xxv) (R Al oR' Lie H\ cH-(cH) -(CH -R R -Al-R H (XXVI) o ll (mint) 0 0 ll z-c-R' H on l c c H CIH-(C ZM -(CHQ -R R oR' 1 (XXVIII) o 0 ll z-c-a H 2)n1 C H-(cm -(caQ -R on R;

(xxIx) In accordance with the reaction scheme of Flowsheet C, acetylene (XVII) is treated with a cycloalkyl, or a (XX). Reduction of the keto function in (XX) with sodium borohydride furnishes the alcohol (XXII), which is then blocked with the triphenylmethyl group or a triphenylmethyl group substituted with one or two methoxy groups. Introduction of the methoxy group (s) increases the rate of etherification and more importantly increases the facility by which acid hydrolysis later cleaves the trityloxy group. Blocking the hydroxy function can also be accomplished with a trialkylsilyl group, a tetrahydropyranyl group, a-alkoxyethyl group or any other hydroxy blocking group compatible with the conjugate addition process described below and which can later be removed by conditions to which the final products (XXIX) are stable.

Alternatively, trans-l-alkenyl iodide (XXII) can be obtained from the aldehyde (XXIII) by reaction of (XXIII) with lithio acetylide and treatment of the resulting 3-hydroxy terminal acetylene (XXIV) with disiamylborane followed with trimethylamine oxide and then with iodine and sodium hydroxide solution.

Submission of the blocked vinyl iodide (XXI) to metal interchange with an alkyl lithium, e.g., n-butyl lithium, at very low temperatures, e.g. 7 8C., provides the vinyl lithium derivative (XXV), the transconfiguration of the double bond being retained. After one to four hours, addition of a trialkyl aluminum, preferably trimethyl aluminum, to the solution of the lithio derivative (XXV) furnishes the key alanate intermediate (XXVI), also with retention of the transconfiguration of the double bond. The cycloalkenone (XXVII) dissolved in ether -or other non-prototropic solvent, is then added to the alanate solution. The resulting solution is allowed to warm to room temperature and is kept for about six to eighteen hours at ambient temperatures. The carboxylic acid group in cycloalkenone (XXVII) is blocked as an ester. Interaction of alanate (XXVI) with cycloalkenone (XXVII) results in the transfer of the trans-l-alkenyl ligand in (XXVI) with retention of the trans-configuration to the cycloalkenone (XXVII) furnishing, after quenching the reaction solution, the l,4-conjugate addition product (XXVIII). In (XXVIII) we are not certain of the relative configuration of the side-chains to each other. The situation is indicated in structure (XXVIII) by the bond between the ring and the chain and is indicated in the nomenclature of the compounds involved by the designation 85. In any event deblocking to (XXIX) with acid, e.g., treatment with acetic acidztetrahydrofuranzwater in the ratio of 3: l :l at 3545C. for sdrne 3 to 48 hours, results in the trans relationship between the chains. This procedure results in de-O-tritylatio'n as well as hydrolysis of tetra- I hydropyranyl and trialkylsilyl groups. Alkyl esters are not cleaved by this procedure. Saponification can be accomplished by the usual alkaline procedures.

In order to ensure a trans-relationship in (XXVIII) these products can be submitted to conditions known in the literature to equilibrate cis-8-iso PGE; to a mixture containing about of the trans product. These conditions involve treatment with potassium acetate in aqueous methanol for 96 hours at room temperature.

The l3-dihydro derivatives (C -C is ethylene) of this invention can be prepared by reduction of the A function in the corresponding l3-prostenoic acids or esters. This reduction can be accomplished by catalytic reduction, preferably at low pressure with a noble metal catalyst in an inert solvent at ambient temperatures.

The l3-dihydro derivatives can also be prepared by treating cycloalkenones of formula (XXVlI) with Grignard reagent (XXX) in the usual manner in the presence of a catalyst such as the tributylphosphine cuprous iodide complex. The l5-O-t-butyl blocking group in the conjugate addition product can be efficiently removed by treatment with neat trifluoroacetic acid in the cold for about twenty minutes followed by brief treatment with aqueous ammonia because of potential 1 S-O-trifluoroacetylation.

1 (xxx) follows and in which Z, R n, s, t, R, R R and C -C are as hereinabove defined.

When the reduction of the 9-keto function is carried out with lithium perhydro-9b-boraphenylalyl hydride [l-l. C. Brown and W. C. Dickason, Journ. Amer. Chem. Soc., 92 709 (1970)] the product is at least predominantly the 9a-hydroxy derivative (XXXII), wherein the 9-hydroxy group is cis to the side-chain attached to C and to the 1 l-substituent if present. In accordance with accepted convention, an a-substituent at the 8-, 9-, l lor l2-positions is behind the plane of the paper whereas a ,B-substitutent at these positions is in front of the plane of the paper. This is usually represented by a M bond for an'a-substituent, a bond for a B-substituent, and a bond where both are indicated.

FLOWSHEET D R7 01 I (CH) -(CH -R I OH (XXXII) A useful procedure for the introduction of the 15- lower alkyl group (R is illustrated by the sequences of Flowsheet E, which follows.

15 gowsHEET E H OH I t ll a "'C"R'3 H i I (CH C C CH/(CH) -(CH -R I i H on (xxxrv) C1 CN (xxxv) ,az-c-a' 3 c H21, ,,c (cm cng -a a ll H OSi(CH z-c\ I R H g a (CH2 n C4C C (CH)t-(CH2) .-R

H u v o 1 (xxxvn) In Flowsheet E above R, R R' R ,n, s, t and Z are as hereinabove defined. In the sequence depicted in Flowsheet E and the 9,15-diol (XXXIV) is treated with 2,3-dichloro-5,o-dicyanobenzoquinone (DDQ) (XXXV), which preferentially oxidizes the allylic alcohol function at C to give the l5-ketone (XXXVI). Blocking of the remaining hydroxy function as a trimethylsilyl ether gives (XXXVlI) which is reacted with the alkyl Grignard, R Mgl, to give the -alky1-15- hydroxy derivative (XXXVlll). Hydrolysis of the silyl ether blocking group then furnishes the diol ester (XXXlX), saponification of which gives (XLl). Oxidation of the secondary 9-hydroxy function in (XX'XIX) provides the 15-alkyl-9-oxo ester (XL), saponification of which furnishes (XLIl).

This procedure leads to two epimeric C alcohols and these are separable by chromatographic procedures.

This invention also embraces the novel and useful intermediates illustrated by the generic formula A below, in which R-,, s, t, R and R are as hereinabove defined with the only proviso being that when R is a 3- numbered carbocycle the sum of s and t is at least one; and K is iodine, lithium, or lithio tri (lower alkyl) alu- The novel compounds of the present invention have potential utility as hypotensive agents, anti-ulcer agents, agents for the treatment of gastric hypersecretion and gastric erosion, periodontal disease, glacoma, uveitis, bronchodilators, antimicrobial agents, anticonvulsants, abortifacients, agents for the induction of 1abo'r, agents for the induction of menses, fertilitycontrolling agents, central nervous system regulatory agents, salt and water-retention regulatory agents, diuretics, fat metabolic regulatory agents, serumcholesterol lowering agents, anti-inflammatory agents and as agents for the inhibition of platelet aggregation. Certain of the novel compounds of this invention possess utility as intermediates for the preparation of other of the novel compounds of this invention.

The compounds of this invention provide protection against the ulcerogenic properties of indomethacin. This assay was carried out in the following manner.

Rats were starved for 48 hours (water was given ad libitum). lndomethacin mg./kg of bodyweight) was adiminstered by the subcutaneous route and one-half the dose of the test compound was administered by gavage at the same time. After three hours, the second half of the test compound was administered also be gavage. Five hours after the administration of indomethacin the animals were decapitated and the stomachs removed. The stomachs were washed with distilled water, blotted on gauze, cut along the larger curvature, and the contents rinsed with distilled water. The stomachs were spread out, pinned on a cork and visualized under magnifying glass for ulcers. The criteria for scoring of ulcers was as previously reported. [Abdel-Galil, et al., Brit. J. Pharmac. Chemotherapy 3321-14 (1968)].

Score 0 Normal stomach I petechial hemorrhage or pin point ulccr 2 l or 2 small ulcers 3 Many ulccrs, a few large 4 Many ulcers, mainly large Control animals treatedv with indomethacin but not test compound consistenly give scores of about 3.0. Control animals treated with neither indomethacin nor test compound give scores of about 0.5-0.8. The results obtained in this assay with typical compounds of the present invention are set forth in Table A below. Compounds producing a lowering of the control score by 0.5 or more are considered to be active.

TABLE A Total Oral dose; mgJkg.

of body Score Compound weight Treated Control 9-oxo-15-hydroxy- 17,20-methanel 3- 12.5 1.8 2.8 trans-prostenoic acid 9-oxo-15-epihydroxy-l7;20- 25.0 1.7 3.0 methane-l3- trans-prostcnoic acid Bronchodilator activity was determined in guinea pigs against bronchospasms elicited by intravenous injections of S-hydroxytryptamine, histamine or acetylcholine by the Konzett procedure. [See J. Lulli'ng, P. Lievens, F. El Sayed and J. Prignot, Arzneimittel- Forschung, 18, 995 (1968).]

In the Table which follows bronchodilator activity for representative compounds of this invention against one or more of three spasmogenic agents is expressed as an ED determined from the results obtained with three logarithemic cumulative intravenous doses.

The novel compounds of the present invention are useful as hypotensive agents and their prostaglandinlike hypotensive activity was demonstrated in the following test procedure. This procedure is a modification of the technique described by Pike, et al., Prostaglandins, Nobel Symposium 2, Stockholm, June, 1966; p. 165.

Male Wistar strain rats Royal Hart Farms) averaging approximately 250 grams in weight were fastened to rat boards in a supine position by means of canvas vests and limb ties. The femoral area was infliltrated subcutaneously with lidocaine and the iliac artery and vein were exposed and cannulated. Arterial blood pressure (systolic/diastolic) was recorded suing a Statham P Db pressure. the animals were anethetized before use with pentobarbital. 30 mg./kg. of body weight intravenously. and also were given hexamethoxium bitartrate, 2 mg./l\'g. of body weight intravenously. The test compounds were prepared by ultrasonic dispersion in a saline-Tween 80 vehicle. A constant intravenous dose volume of 0.5 ml. was administered and test doses ranged from 0.1 to 10.0 mg./kg. of body weight. Inreasing or decreasing doses were selected depending on the dose response obtained. In Table C below are set forth the minimal doses required to produce a decrease of about mm. in diastolic blood pressure for typical compounds of the present invention.

TABLE C HYPOTENSIVE ACTIVITY Minimal elTective hypotensive dose Compound (mg/kg. of body weight) 9-oxol S-hydroxyl 7,20- methano-l 3-transprostenoic acid 9-oxol S-epi-hydroxyl7,20-methano- 3-transprostenoic acid 1 9-oxo-15-hydroxy-l6- methyl-l 8,20-ethanol 3- trans-prostenoic acid 9-oxo- 1 S-hydroxyl 6.20- methano-l 3-transprostenoic acid 0.2

9-oxol S-hydroxyl 6,20- 1,3-propano )-5-cis,-

l S-Irans-prostadicnoic acid 9-oxol S-hydroxyl 5- methyl-l 8.20-cthano- 5-cis, l 3-trans-prostadienoic acid 9-oxol S-hydroxy-cis- 17.1 8-methano-l3-transprostenoic acid 9-oxo-7a 7 b-hishomol 5 hydroxy-cisl 7.1 8- methano-prostenoic acid 9-oxol S-hydroxy-cisl 7,- l8-mcthano-5-cis, l 3 trans-prostadienoic acid 9-oxol S-hydroxy-l 5- mcthyl-cisl 7,1 8- methano-S-cisJ 3-transprostadienoic acid l This invention will be described in greater detail in conjunction with the following specific examples.

In the following examples. unless otherwise indicated, the products obtained include all possible optical isomers.

EXAMPLES 1 Preparation of 2-(6-carbethoxy-6-fluorohcxyl)cyclopent-Z-en-l-one This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carbethoxyoctyl)cyclopent- 2-en-l-one by substituting diethyl fluoromalonate for diethyl ethylmalonate.

EXAMPLE 2 Preparation of 2-(6-carbethoxy-6- phenylhexyl)cyclopent-2-en-1-one This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-( 6-carbethoxyoctyl)cyclopent- 2-en-l-one by substituting diethyl phenylmalonate for diethyl ethylmalonate.

EXAMPLE 3 Preparation of 2-(6-carbethoxy-heptyl)cyclopent-2- en-l-one I This cyclopentenone is prepared by the procedure described in Belgium Pat. No.'786,215 (Jan. 15. 1973) for the preparation of 2-(6-carbethoxyoctyl)cyclopent- 2-en-1-one by substituting diethyl methylmalonate for diethyl ethylmalonate.

EXAMPLE 4 EXAMPLES 5-7 Treatment of 2-(6-carboxyhexyl)cyclopent-Z-enl-one by the procedure of Example 5 with the appropriate alcohol affords theester's of the following table.

TABLE 1 Example Alcohol Product Ester 5 isopropanol 2-(o-carboisopropoxyhexyl )cyelopent-Z-en- 1 -one 2-( 6-carbomethoxyhexyl )cyclopent-Z-en- 1 -one decyloxyhexyl )eyclopent-Z-enl one.

6 methanol 7 l-hydroxy-n-deeane EXAMPLE 8 Preparation of 2-carbalkoxy (methyl/ethyl)-2-(2- methoxyethyl)-cyclopentan-l-one Treatment of 2-cyclopentenone carboxylate (mixed methyl and ethyl esters) with 2-methoxyethyl bromide by the method of Example 1 of Belgium patent No. 786,215 furnishes the subject compound as an oil, b.p. C. (0.1 mm).

EXAMPLE 9 Preparation of 2(Z-methoxyethyl)cyclopentanl-one ample 2 of Belgium Pat. No. 786,215 furnishes the subject compound as an oil, b.p. 4550C. (0.02 mm).

EXAMPLE Preparation of 1-acetoxy-2-(2-methoxyethyl)cyclopent-l-ene The subject compound is prepared from 2-(2- methoxyethyl)cyclopentan-l-one (Example 9) and acetic anhydride by the procedure EXAMPLE 1 1 Preparation of 2-(2-hydroxyethyl)-cyclopent-2-en- 1-one The enol acetate of Example 10 is brominated and dehydrobrominated by the method described in Example 28 of Belgium Pat. No. 786,215. The crude product is then dissolved in methylene chloride and is added at 78C. to a methylene chloride solution containing about seven molar equivalents of boron tribromide. After one hour at 78C. the solution is allowed to warm to room temperature and is then kept at ambient temperatures for a total of eighteen hours. The mixture is poured into water and extracted with ether. The organic phase is washed with saturated saline solution. then water and is dried. Evaporation of solvents leaves subject product, which is purified by distillation. The combined organic phases are washed with ice cold 5% sodium hydroxide solution, ice cold 5% hydrochloric acid, and saturated sodium chloride solution. dried with anhydrous magnesium sulfate and taken to dryness. Distillation gives a pale yellow oil; A max 5.85 t

(carbonyl group).

EXAMPLE 12' Preparation of 2-formy1methylcycopent-2-en-1one Chromium trioxide (0.6 mol) is added to a stirring solution of (1.2 mol) of anhydrous pyridine in 1,500 ml. of anhydrous methylene chloride cooled in an ice bath. The deep red suspension is stirred for 15 minutes at 0C. and 45 minutes at ambient temperature. A solution of 01.5 mol of 2-(2-hydroxyethyl)-cyclopent-2-enl-one (Example 11) in 50 ml. of methylene chloride is added, all at once, to the suspension. A black terry deposit is formed immediately. After stirring the mixture for 25 minutes at ambient temperature, the methylene chloride is decanted from the tarry precipitate which is then triturated several times with ether.

EXAMPLE 13 Preparation of 2-(6-carboxy-2-cis-hexenyl)-cyclopent-2-en- 1 one A mixture ofO. 194 g. (0.007952 mole) of sodium hydride (free of mineral oil) and 5.5 ml. of dimethylsulfoxide is heated to 70C. until gas evolution ceases under a nitrogen atmosphere. The resulting solution is cooled below room temperature and treated with a solution of 1.400 g. (0.00316 mole) of 4-carboxybutyltriphenyl phosphonium bromide [E. J. Corey, et al., J. Am. Chem. 500., 91, 5675 (1969)] in 6 ml. of dimethylsulfoxide. To the resulting red solution is added 0.00263 mole of 2formylmethylcyclopent-Z-en-l-one (Example 12) in 2 ml. of dimethylsulfoxide and the mixture is stirred at room temperature for 2.25 hours. The mixture is poured into icewater. sodium hydroxide solution is added to pH 12, and the neutral materials are extracted with diethyl ether. The basic phase is acidified with dilute hydrochloric acid and is extracted with diethyl ether. The organic phase is washed with water and saturated brine, dried (Na SO and evaporated to a semicrystalline mass.- The latter is triturated with hot hexane, the solids are filtered off, and the filtrate is evaporated to yield the subject product as an oil. 0

EXAMPLE '14 EXAMPLE 15 Preparation of 1-oxa-2-hydroxy-bicyclo[3.3.0loct- 4-ene A solution of 6.2 g. (50 mole) of the lactone of cis-2- hydroxycyclopent-4-ene-l-acetic acid [P. A. Grieco, J. Org. Chem., 37, 2363 (1972)] in 350 ml. toluene (dried over molecular sieves) is cooled to C. and treated dropwise under nitrogen with 84 ml. 0.89 M diisobutyl aluminum hydride (10.55 g., 74 mole) over a period of about one hour maintaining the temperature at 74 1 2C. The resulting clear solution is stirred at -75C. for two hours and poured with stirring into a mixture of 15 ml. of concentrated hydrochloric acid and 300 ml. of ice water. The mixture is stirred while warming to room temperature. The layers are separated and the aqueous layer is treated with salt andextracted with three small portions of ether. The combined organic portions are dried over sodium sulfate and evaporated at reduced pressure (75C. water bath) to yield the product (homogeneous by thin layer of chromatography) as a pale yellow mobile liquid.

EXAMPLE 16 Preparation of 1-hydroxy-2-( 6-carboxy-2-cishexeny1)cyclopent-3-ene A solution of the sodium salt of dimethyl sulfoxide is prepared by stirring under nitrogen a mixture of ml. dry dimethyl sulfoxide (dried over molecular sieves and a few pellets of calcium hydride) with 6.0 g. (0.25 mole) of sodium hydride (prepared by making 10.5 g. of 57% sodium hydride dispersion in mineral oil with two 30 m ll portions of hexane.) The mixture is warmed with stirring at 75C. (oil bath) for 2.5 hours.

A This solution is added during five minutes to a solution under nitrogen of 44 grams (0.1 mole) of 4- carboxybutyltriphenylphosphonium bromide (Example 18A) in m1. of dry dimethyl sulfoxide. The resulting dark reddish brown solution is stirred for ten minutes, cooled to room temperature and treated with a solution of crude 1-oxa-2-hydroxy-bicyclo[3.3.0loct- 4-ene (6.2 g., 50 mole) (Example 15) in 20 ml. ofanhydrous dimethyl sulfoxide. The resulting solution is stirred 16 hours and then treated with 250 ml. ice water.

This brown solution is extracted with two portions of ether to remove neutral material then made strongly acidic with hydrochloric acid. The solution is extracted into four lOO ml. portions of methylene chloride. The combined methylene chloride extracts are mashed with water, then extracted with four 100 ml. portions of sodium bicarbonate. The combined aqueous extracts are mashed with methylene chloride and made acidic to Congo Red with concentrated hydrochloric acid. The mixture is extracted with three 100 ml. portions of methylene chloride. The organic extracts are combined, dried over sodium sulfate and the solvent is evaporated at reduced pressure. The residue (an oily solid) is extracted several times with ether and the ethereal extracts are combined and evaporated at reduced pressure to yield the crude product as a dark oil. The product is purified by chromatography on silica gel, eluting in the ether. The product is a colorless liquid.

EXAMPLE 17 EXAMPLE 18 Preparation of 2-(6-carboxy-2-cis-hexenyl)cyclopent-2-en-l-one A solution of 3 g. of crude 2-(6-carboxy-2-cishexenyl)cyclopent-3-en-l-one (Example l7) in 100 ml. of 2% sodium hydroxide is stirred at 80C. under nitrogen for 1.5 hours. The cooled solution is acidified to Congo Red and extracted with ether. The ethereal extracts are dried over sodium sulfate and evaporated at reduced pressure to afford'the product.

EXAMPLE 18A Preparation of 4-carboxybutyltriphenylphosphonium bromide A mixture of 103 g. of S-bromoval eric acid and 152 g. of triphenylphosphine in 400 ml. of acetonitrile is refluxed for 48 hours, cooled, diluted with 100 ml. of benzene and allowed to crystallize. The crystals are filt'ered, washed with benzene and ether, to yield colorless material, m.p. 207-209C.

EXAMPLES l8B-l 8D Treatment of the indicated w-bromoalkanoic acids of Table 3A below with triphenylphosphine by the method described in Example 18A produces the phosphonium bromides of the table.

TABLE 2 Starting m-bromo Product Example alkanoic acid phosphonium bromide 18B 4-bromo-n-butyric 3-carboxypropyltriphenylphosacid phonium 18C .-bromo-n-hcxanoic 5-carboxypentyltriphenylphosacid phonium bromide 18D 7-bromo-n-heptanoic 6-carboxyhexyltriphenylphosacid phonium bromide EXAMPLES 19-21 Treatment of l-oxa-2-hydroxy-bicyclo[3.3.0]oct- 4-ene by the procedure described in Example 16 with the ylids derived from the phosphonium bromides listed in Table 3 below furnishes the product lhydroxy-cyclopent-3-enes of the table.

TABLE 3 Product l-hydroxy-2-( w-carboxy-Z-cisalkcnyl )cyclopent-B-enes Starting phosphonium bromide of Example Example l9 l 88 l-hydroxy-2-( 5-carhoxy-2-cispentyl )cyclopent-B-ene 20 18C l-hydroxy-2-( 7-carhoxy-2-cisheptcnyl)cyclopent-3-enc I 21 18D l-hydroxy-2-( 8-carboxy-2-cis- I octenyl )cyclopent-3-ene EXAMPLES 22-24 Oxidation of the l-hydroxycyclopent-3-enes listed in Table 4 below by the procedure described in Example 17 is productive of the product cyclopent-3-en-l-ones of the table.

EXAMPLES 25-27 Base treatment according to the procedure described in Example 18 of the cyclopent-3-ene-1-ones listed in Table 5 below is productive of the product cyclopent- 2-en-l-ones of the table.

TABLE Example Starting Product Z-(w-earhoxy-Z-cis- Z-(arcarhoxyQ-cisalkenyl )cyclopentalkenyl )cyclopent-Z-en- I -one 3-ene-l-one of Example "5 22 2-( 5carboxy-2-cis-pentcnyl )cyclopent-2-en-l-one 26 23 2-(7-carbnxy-Z-cis-hcptenyl)cyclopent-Z-en- I -one 27 24 2-( S-carboxy-fZ-cisoctenyl )cyelopent-2-en- 1 -one EXAMPLES 28-30 Treatment of the listed Z-(w-carboxy-Z-cisalkenyl)cyclopent-2-en-l-one of Table 6 below with diazomethane in the usual manner is productive of the product methyl esters of the table.

TABLE 6 Product 2-( w-carbomethoxy-2-cisalkenyl )cyclopent-2-enl-one Example Starting carboxylic acid of Example 28 25 2-( 5-carhomethoxy-2-cispentenyl )cyclopent-Z-en- I -one 29 26 2-( 7-carhomethoxy-2-cishcptcnyl )cyclopent-Z-enl-one 3U 27 2-( 8-carhomethoxy-2-cisoctenyl )cyclopent-Z-enl -one EXAMPLE 31 EXAMPLE 32 Preparation of 1-chloro-4-cyclopentyl-1-trans-buten- 3-one A three-necked flask fitted with a stirrer. a gas inlet tube and a gas outlet tube protected with a calcium chloride tube is surrounded by an ice-water bath. The system is flushed with acetylene for 3 minutes. Carbon tetrachloride (150 ml.) is added to the flask and acetylene is bubbled through at a fast rate for 3 minutes. Aluminum chloride (59 g.) is added and acetylene is bubbled through the mixture for 5 minutes. The gas inlet tube is replaced by a dropping funnel protected by a calcium chloride drying tube. Cyclopentylacetyl chloride (55.4 g.. Example 1) is added to the reaction mixture stirring over a period of about 20 minutes. The dropping funnel is replaced by the gas inlet tube and with stirring. acetylene gas is bubbled through at a rate in excess of the saturation rate. After about 15 minutes the rate of absorption of acetylene suddenly becomes very rapid. and the acetylene is passed through as rapidly as it is absorbed. The introduction of acetylene is continued for minutes after the rapid absorption (which lasts about 1 hour) has subsided.

The reaction mixture is poured with stirring onto 430 g. of ice and 180 ml. of saturated sodium chloride solution. The aqueous phase is extracted three times with ether. The combined extracts are dried with anhydrous magnesium sulfate and evaporated to dryness in vacuo.

After addition of 1.5 g. of hydroquinone the residual oil is distilled to give 57 g. (80%) of oil. b.p. 6769C. (0.14 mm.).

EXAMPLE 33 Preparation of 4-cyclopentyl-l-iodo-lTrans-buten- 3-one A solution of 57 g. of l-chloro-4-cyclopentyl-transbuten-3-one (Example 32) in 360 ml. of acetone containing g. of sodium iodide is stirred at the reflux temperature for 18 hours. The resulting mixture is cooled, filtered and and the water liquor is taken to dryness. The residual oil is dissolved in ether washed successively with water. dilute sodium thiosulfate solution, and saturated sodium chloride solution. dried with anhydrous magnesium sulfate and taken to dryness to give 87g. (99%) of orange oil. Vapor phase chromatography shows one peak.

EXAMPLE 34 Preparation of 4-cyclopentyl- 1 -iodol -trans-buten-3- To a solution of 7.1 g. of sodium borohydride in 6( ml. of absolute alcohol. stirred in an ice bath under nitrogen atmosphere. is added dropwise. over a period ol about 2 hours. a solution containing 7 g. of 4- cyclopentyl-l-iodo-1-trans-buten-3-one (Example 3 3 j in 160 ml. of absolute alcohol. The temperature is maintained atj 5l 0C. The solution is poured into 85C ml. of iced water and the resulting mixture is extractec three times with ether. The combined extracts are washed with dilute sodium bisulfite solution. saturatec sodium chloride solution. dried with anhydrous magnesium sulfate and taken to dryness to give 81 g. of yellow oil. Column chromatography on a column of 1 kg. 01 silica gel using benzene gives g. (88%) of oily prodact. 40

EXAMPLES 35 58 Treatment of the carboxylic acids in Table 1 below with thionyl chloride by the procedure disclosed in Example 31 followed by treatment of the resulting acid chloride with acetylene by the procedure described in Example 32. and thence by treatment of the resulting l-chloro-ltrans-alkene-3-one with sodium iodide by the procedure described in Example 33. and then by treatment of the resulting l-iodo-l-trans-alkene-3-one with sodium borohydride by the procedure described in Example 34 is productive of the product 3-hydroxy-liodo-l-trans-alkenes of the table.

Table 1 Product 3-hydroxyl -iodol -trans- 'alkene Example Starting Carboxylic acid 3-Cyclopentylpropionic acid 4-Cyclopentylbutyric acid 5-Cyclopentylpentaaoic acid o-Cyclopentylhcxanoic acid Z-Methyl-S- cyclopentylpropanoic acid Table l-Continued Example Starting Carboxylic acid Product 3-hydroxy- I -iodo- I -transalkene 42 (Z-trans-methylcyclopentyl)acetic acid 43 4-( 2-trans'methylcyclopentyl)butyric acid 44 Cyclohexylacetic acid 45 3-Cyclohcxylpropionic acid 46 4-Cyclohexylhutyric acid 47 Cycloheptylacetic acid 48 (4-methylcyclohcptyl )acetic acid 49 Cyclooctylacetic acid",

5O (4-methylcyclohexyl )acetic acid" 5 I (3-methylcyclohexyl )acetic acid" 52 3-Cycloheptanc carboxylic acid 53 Cyclopentane carhoxylic acid 54 Trans-2-mcthylcyclo entane carboxylic acid 2 55 all-trans-Z.3-dimethylcyclopentane carboxy ic acid 56 Cyclohexanc carboxylic acid 57 Trans-4- methylcyclohexane carboxylic acid 58 Cyclooetane carboxylic acid 4-( 2-trans-methylcyclopentyl 3-hydroxyl -iodo- I -transbutene 6-( Z-trans-methylcyclopentyl 3-hydroxy- I -iodo' I -trans hexene 4-Cyclohexyl-3-hydroxy- I iodo- I -trans- I -trans-butene 5-cyclohexyl-3-hydroxyl -iodol-trans-pentene 6-cyclohcxyl-3-hydroxy- I -iodo- I -trans-hexene 4-Cyclohcptyl-3-hydroxy- I iodol -trans-butene 4-( 4-methylcycloheptyl )-3- hydroxy- I -iodo- I -trans-butene 4-Cyclooctyl-3-hydroxyl iodo- I -trans-butene 4-( 4-methylcyclohexyl )-3- hydroxy-l -iodol -trans-butene 4-( 3-methylcyclohexyl )-3- hydroxy- I -iodo- I -trans-butene 3-Cycl0heptyl-3-hydroxyl iodol -trans-propene 3-Cyclopentyl-3-hydroxy- I iodol -trans-propene 3-( Trans-Z-methylcyclopentyl 3-hydroxy- I -iodol -tran$- propenc 3-( all-trans-2,3-dimethylcyclopentyl I 32 iodo- I -trans-propene 3-Cyclohcxyl-B-hydroxy- I iodo- I -trans-propenc 3-( trans-4-methylcyclohcxyl 3-hydroxy- I -iodo- I -transpropene 3-Cyclooctyl-B-hydroxy- I iodo- I -trans-propenc C. G. Overberger et al., J. Polymer Sci., Pt. A, 2, 755( I964) 2 M. I. Goryaev et al., Chem. Abs., 69, I742, No. I86462 (I968).

C. D. Nenitzescu and G. G. Vantu, Bull. Soc. Chim.

France [5]. 2, 2209 (1935). 4G. R. Yohe and R. Adams, J.

Amer. Chem. 800., 50, I503 (I928).

5 W. Herz, J. Org. Chem.,20, I062 (1955).

G. S. Hiers and R. Adams. J. Amer. Chem. Soc., 48, 2385 E. E. Royals and A. N. Neal, J. Org. Chem., 21, I448 (I956).

** F. F. Blicke and W. K. Johnson, J. Am. Pharm. Assoc. Sci. Ed.,

9 L. 9R3uzicka and H. A. Bockeno'ogen, Helv. Chim. Acta, I4, 13 I 9 A. W. Burgstahler and I. C. Nordin, J. Amer. Chem. Soc., 83,

I98 (l96l i J. von Braun and W. Teufiert, Ber. 58B, 2210 (I925).

M. Julia and F. LeGoffe, Bull. Soc. Chim. Fr., 1550 (l965).

' V. N. lpatieff et al., J. Amer. Chem. Soc., 75, 6222 (I953).

A. T. Blomquist and F. W. Sehlaefe, J. Amer. Chem. Soc., 83,

EXAMPLE 59 Preparation of 4-cyclopentyl-I-iodo-3-triphenylmethoxyl trans-butene A mixture of 21.4 g. of 4-cyclopentyl-l-iodo-transbuten-3-ol (Example 34) in 170 ml. of dry pyridine containing 31 g. of triphenylmethyl bromide is heated on the steam bath for 2 hours. The dark mixture is poured into 850 ml. of iced water and the resulting sogives 32 g. (78%) of syrup which solidifies on standing. Recrystallization from hexane affords white crystals, m.p. 8788C.

EXAMPLE 60 Preparation of 4-cyclopentyll -iodo-3-(pmethoxyphenyldiphenyl )-methoxyl -trans-butene A solution of 20 g. of 4-cyclopentyl-l-iodo-l-transbuten-3-ol (Example 34) and 25 g. of panisylchlorodiphenylmethane in 170 ml. of dry pyridine is kept at 60C. for 18 hours, then at C. for 3 hours. The cooled solution is poured into 850 ml. of iced water. The resulting solution is partitioned between ether and water. The ether layer is washed with water, dried with anhydrous magnesium sulfate and taken to dryness. Further evaporation with toluene removes residual pyridine. The resulting oil is chromatographed on 300 g. of florisil with hexanes to give 22.3 g. of product. The material is homogeneous according to thin layer chromatography.

EXAMPLES 6l 84 Treatment of the listed 3-hydroxy-l-iodo-trans-lalkenes of Table 2 below with triphenylmethylbromide by the procedure described in'Example 59 above is productive of the product 3-triphenylmethoxy-l-iodotrans-l-alkenes of the table.

Table 2 Example Starting Product 3-hydroxyl -iodo- I 3 triphenylmethoxy- I -iodo-trans- I trans-alkene of alkene Example 6 I 35 4-Cyclobutyl-3-triphenylmethoxy- I iodo- I -trans-butene 62 36 5-Cyclopentyl-3-triphenylmethoxyl -iodo- I -transpentene 63 37 6-Cyclopentyl-3-triphenylmethoxyv I -iodol -trans-hexene 64 38 7-Cyclopentyl-3-triphenylmethoxyl -iodo- I -trans-heptene 65 39 8-Cyclopentyl-3-triphenylmethoxy- I -iodol trans-octane 66 40 S-Cyclopentyl-4-methyl-3- triphenylmethoxy- I -iodo- I -transpentene 67 4! 6-Cyclopentyl-4-ethyl-3- triphenylmethoxyl-iodol -transhexene 68 42 4-( 2-trans-methylcyclopentyl )-3- triphenylmethoxyl -iodo- I -transbutene 69 43 6-(2-trans-mcthylcyclopentyl)-3- triphenylmethoxy- I -iodol -transhexene 70 '44 4-Cyclohexyl-3-triphenylmethoxy- I -iodol -trans-butene 7 l 45 5-Cyclohcxyl-3-triphenylmerhoxy- I -iodol -trans-pentene 72 46 6-Cyclohexyl-3-triphenylmethoxyl-iodol -trans-hexane 73 47 4-Cycloheptyl-3-triphenylmethoxy- I -iodol -trans-butene 74 48 4-(4-methylcycloheptyl )-3- triphenylmethoxyl -iodo- I -transbutene 75 49 4-Cyclooctyl-3-triphcnylmethoxyl iodol -trans-butene 76 50 4-(4-methylcyelohexyl)-3- triphenylmethoxyl -iodo- I -transbutene 77 5 I 4-( 3-methylcyclohexyl)-3- triphenylmethoxyl -iodo- I -transbutene 78 52 3-Cyclohcptyl-S-triphenylmethoxyl'iodo-trans-propene 79 53 3-Cyclopentyl-3-triphenylmcthoxy- I -iodo- I -trans-propene 80 54 3-(trans-2-methylcyclopentyl)-3- triphenylmethoxyl -iodo- I -transpropene Table 2 Continued Example Starting Product 3-hydroxy-1-i0do-1- B-triphenylmethoxyl -iodotrans-alkene of trans-l-alkene Example 81 55 3-(all-trans-2,3-

dimethylcyclopentyl )-3- triphcnylmethoxy- 1 iodol -transpropene 82 56 3-Cyclohcxyl-3-triphenylmethoxyl-iodol -trans-propene 83 57 3-(transl-methylcyclohexyl )-3- triphcnyl-mcthoxy- I -iodol -transpropene 84 5 8 3-Cyclooctyl-3-triphenylmethoxyl iodol -trans-propene EXAMPLE 84A Preparation of 1,1-dimethyl-cis-3 ,4-

methylenehexane (cis-1-ethy1-2-(2,2- dimethoxyethyl)cyclopropane To an ethereal suspension of zinc-silver couple, prepared according to the procedure of J. M. Denis, G. Girard, and J. M. Conia (Synthesis, 1972, 549) from 0.400 g. of silver acetate, 400 ml. of acetic acid, 68 g. of granular zinc, silver wool, and 600 ml. of ether is added dropwise 136 g. of diiodomethane at a rate to mainatin a gentle reflux. The mixture is then stirred at room temperature for 1 hour and to it is then added 57.7 g. of l,l-dimethoxy-cis-3-hexene. [(M. Winter, Helvetica Chimica Acta, 46, 1792 1963)] over a period of minutes and the mixture is refluxed for 5 hours. The mixture is cooled to 0C., 600 ml. of ether is added followed by 50.5 g. of pyridine dropwise over a period of 1 hour. The resulting precipiate is filtered and washed with ether. The filtrate and washings are combined and evaporated and the residue is fractionally distilled at 12 torr to yield the title compound as a colorless oil.

EXAMPLE 84B Preparation of cis-3,4-methylene- 1 -hexanol To a vigorously stirred solution of 31.6 g. of 1,1- dimethoxy-cis-3,4-methylene-hexane (Example 84A), 75 mg. of hydroquinone, 6 g. of oxalic acid in 150 ml. of acetone heated at 45C. under an inert atmosphere is added 700 ml. of water over a period of 0.5 hours. The mixture is cooled and extracted well with ether. The organic phase is separated, washed with saturated sodium bicarbonate solution and saturated brine, dried (Na SO and evaporated. The residue is distilled at 30 torr. to yield the title compound.

EXAMPLE 85 Preparation of cis-5,6-methylene-1-octyn-3-ol To a solution of 15.2 g. (0.165 mole) of lithium acetylide-ethylenediamine complex in 100 ml. of dry dimethylsulfoxide is added 16.8 g. (0.150 mole) of cis-3,4-methylene-l-hexanol (Example 84B) in m. of dimethylsulfoxide at a rate to maintain a temperature of 25C. (cooling). The mixture is then maintained at 25C. for 2 hours and is poured onto ice and excess hydrochloric acid. The mixture is extracted with ether and the organic phase is washed with water and saturated brine, dried (Na SO and evaporated to an oil. Distillation in vacuo yields the title compound as a colorless oil.

EXAMPLE 85A 3-triphenylmethoxy-cis-5 ,6-

1 01 (Example and 33.0 g. of triphenylmethyl bro- EXAMPLE 86 Preparation of 1-iodo-3-triphenylmethoxy-cis-5,6-

methylene-transl-octene To 160 ml. of a 0.50M solution of disiamylborane in diglyme cooled to 0C. under an inert atmosphere is added 28.6 g. (0.075 mole) 3-triphenylmethoxy-cis- 5,6-methylene-1-octyne (Example 85A). The mixture is allowed to come to room temperature and is stirred at ambient temperature for 3 hours. The solution is cooled to 0C. and 16.9 g. (0.225 mole) of triethylamine oxide is added portionwise such that the temperature is maintained at 0-5C. The mixture is stirred at 0C. for 1 hour and is then poured into 300 ml. of 1 N sodium hydroxide followed immediately by a solution of 57 g. (0.225 mole of iodine in ml. of tetrahydrofuran. The mixture is stirred at ambient temperatures for 0.5 hour and poured into 1,000 ml. of water. The mixture is decolorized by addition of sodium thiosulfate solution and is extracted into ether. The organic phase is washed with water and the solvent is removed in vacuo. The residue is purified by dry-column chromatography upon 1.5 kg. of alumina using hexane as eluent The title compound is obtained as an oil.

EXAMPLES 87 93B Treatment of the carboxaldehydes listed in Table 3 below with lithium acetylide by the procedure described in Example 85 followed by treatment of the resulting 3-hydroxy-1-alkyne with triphenylmethyl bromide by the procedure of Example 85A furnishes the product 3-triphenylmethoxy-l-alkynes of the table.

\ Table 3 Example Starting Product Table 3 Continued Example Starting Product carboxaldehyde 3-tripheny1-methoxy- 1 alkynes 93 B (adamantyI-1(- 4-( 1adamantyl)-3-triphcnylmcactaldchyde thoxy C. W. Whitehead ct 111., J. Org. Chem. 26, 2814 (1961). A. H. Alhcrts H. Wynbcrg and J. Strating. Synthetic Communications Z, 79 I972).

EXAMPLES 94 100B Treatment of the 3-triphenylmethoxy-l-alkynes listed in Table 4 below with disiamylborane, trimethylamine oxide; iodine and aqueous sodium hydroxide by the procedure described in Example 86 furnishes the product 3-triphenylmethoxyl iodo- 1 trans-alkenes of the table.

Table 4 Example Starting 3-triphenylmethoxyl-alkynes of Example Product 3-tripheny1methoxyl iodo- 1 -trunsalkene propene 4-( l-adamantyl )-3- triphenylmethoxy- 1 iodo- 1 transbutene EXAMPLE 101 Preparation of methyl 9-oxo-l5-hydroxy-l7,20-

methano-l 3-trans-prostenoate l l-deoxy-l 7,20- methanoprostaglandin-E, methylester)) To a solution of 6.35 g. (12.5 mmoles) of 4- cyclopentyl-1-iodo-3-triphenylmethoxy-l-trans-butene (Example 59) in ml. of dry toluene, cooled to 78C. in a nitrogen atmosphere, is added dropwise within 10 minutes, 5.4 ml. (12.5 mmoles) of a 2.34 molar solution of n-butyllithium in hexane. The solution is allowed to warm to 40C. and is maintained at that temperature for 1 hour. The resulting solution containing (3-triphenylmethoxy-4-cyclopentyll transbutenyl)lithium is cooled to 78C. and there is added dropwise 5.15 ml. (12.5 mmoles) of a 2.44 molar solution of trimethylaluminum in heptane. The resulting solution containing lithio (3-triphenylmethoxy-4- cyclopentyl-l-trans-butenyl)trimethyl alanate is allowed to' warm to lOC., cooled to 35C. and there is added dropwise 2.24 g. (10 mmoles) of 2-(6- carbomethoxyhexyl)-2-cyclopentenone (Example 6) in 10 ml. of ether. The 2-phase mixture is then allowed to warm to ambient temperature and is stirred for 18 hours.

The resulting single phase solution is poured cautiously into ice and excess dilute aqueous hydrochloric acid. Ether is added and the organic phase is separated, washed successively with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and evaporated to give 8.35 g. methyl 9-oxo-l5- triphenylmethoxy-17,20-methano-13-transprostenoate as an oil.

The oil is heated under nitrogen atmosphere in 100 ml. of aqueous acetic acid at 80-85C. for 1 hour. The resulting solution is take to dryness then evaporated two times with toluene. The resulting oil is triturated with 15 ml. of hexane and filtered to remove triphenylcarbinol (2.5 g., m.p. l56-158C.). Evaporation of the mother liquor gives 4.8 g. of viscous oil. The oil, dissolved in 2 ml. of methylene chloride, is applied to a dry column (nylon tube, 1 /8 inches flat 33 36 inches) containing 360 g. of silica gel. The column (30 inches long) is developed with benzene-ethyl acetate (4:1). The first and last 3 inches of the column are discarded; the remainder of the column being divided into 1 /2 inch segments. Each of the sixteen segments is triturated with ether, filtered and taken to dryness Segments 1 and 2 give no material. Segments 3, 4 and 5 afford. 512.7'mg. of methyl 9-oxo-15-hydroxy-17,20- methano-l 3-trans-prostenoate( l 1 deoxyl 7,20-

methano-prostaglandin-E, methyl ester); Amax 2.86 (OH), 5.75 (C=O), and 10.25 p. (trans-CH=CH); thin layer chromatography shows one spot, Rf 0.189. Segments 6 and 7 are combined to give 622 mg. of oil which after partition chromatography affords 193 mg. of methyl 9-oxo-1S-epi-hydroxy-17,20-methano-l3- trans-prostenoate 15-epi-1 l-deoxy-17,20- methyleneprostaglandin-E methyl ester); A max 2.86 (OH), 5.75 (C=O), and 10.25 p. (trans--Cl-l=CH); thin layer chromatography shows on spot, Rf 0.266. There is also obtained an additional 237 mg. of 11- deoxy-l7,2O-mthanolprostaglandinE methyl ester identical in all respects to the material found in segments 3, 4 and 5 above. Segments 8 and 9 are combined to give 850.7 mg. of oil which when further purifie by partition chromatography gives 601 mg. l5-epil 1 deoxyl 7,20-methanoprostaglandin-E methyl ester identical with the material obtained above.

EXAMPLE 102 Preparation of 9-oxo-l S-hydroxy-17,20-methano-l3- trans-prostenoic acid( 1 l-deoxyl 7,20-methanoprostaglandin-E A suspension of 512.7 mg. of l 1-deoxy-17,20- methano prostaglandin-E, methyl ester (Example 101) in 10 ml. of methanol-water (1:1) containing 200 mg. of potassium hydroxide is stirred under nitrogen atmosphere at 50C. for 1 hour. The resulting solution is then stirred at ambient temperature for 18 hours. The solution is cooled in an ice-bath, acidified with 1N hydrochloric acid and extracted several times with ether. The combined extracts are washed with saturated sodiumchloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 481 mg. (98% of syrup which crystallizes on standing.

EXAMPLE 1 03 Preparation of 9-oxol S-epi-hydroxy- 1 7,20- 

1. 1-9-OXO-15-HYDROXY-16METHYL-18,20-ETHANO-13-TRANSPROSTENOIC ACID AND THE PHARMACEUTICALLY ACCEPTABLE CATIONIC SALTS THEREOF.
 2. d1-9-Oxo-15-hydroxy-16-methyl-18,20-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 3. 1-9-Oxo-15-hydroxy-16,20-methano-13-trans, 18-prostadienoic acid and the pharmaceutically acceptable cationic salts thereof.
 4. d1-9-Oxo-15-hydroxy-16,20-methano-13-trans, 18-prostadienoic acid and the pharmaceutically acceptable cationic salts thereof.
 5. 1-9-Oxo-10a-homo-15-hydroxy-17,20-(1,3-propano)-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 6. d1-9-Oxo-10a-homo-15-hydroxy-17,20-(1,3-propano)-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 7. 1-9-Oxo-2-methyl-15-hydroxy-16-ethyl-19,20-(1,3-propano)-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 8. d1-9-Oxo-2-methyl-15-hydroxy-16-ethyl-19,20-(1,3-propano)-13-trans -prostenoic acid and the pharmaceutically acceptable cathionic salts thereof.
 9. 1-9-Oxo-3,3-dimethyl-15-hydroxy-16,20-methano-13-trans-prostenoic acid and the pharmaceutically aCceptable cationic salts thereof.
 10. d1-9-Oxo-3,3-dimethyl-15-hydroxy-16,20-methano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 11. 1-9-Oxo-3-oxa-15-hydroxy-16,19-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 12. d1-9-Oxo-3-oxa-15-hydroxy-16,19-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 13. 1-9-Oxo-3-oxa-15-hydroxy-16-ethyl-19,20-(1,3-propano)-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 14. d1-9-Oxo-3-oxa-15-hydroxy-16-ethyl-19,20-(1,3-propano)-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 15. 1-9-Oxo-3-thia-15-hydroxy-16,20-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 16. d1-9-Oxo-3-thia-15-hydroxy-16,20-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 17. 1-9-Oxo-3-thia-15-hydroxy-16-methyl-18,20-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 18. d1-9-Oxo-3-thia-15-hydroxy-16-methyl-18,20-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 19. 1-9-Oxo-15-hydroxy-15-methyl-18,20-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 20. d1-9-Oxo-15-hydroxy-15-methyl-18,20-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 21. 1-9-Oxo-15-hydroxy-15-methyl-17,20-(1,3-propano)-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 22. d1-9-Oxo-15-hydroxy-15-methyl-17,20-(1,3-propano)-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 23. 1-9-Oxo-3-thia-15-hydroxy-15-methyl-17,20-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 24. d1-9-Oxo-3-thia-15-hydroxy-15-methyl-17,20-ethano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 25. 1-Decyl 9-oxo-15-hydroxy-16-methyl-18,20-ethano-13-trans-prostenoate.
 26. d1-Decyl 9-oxo-15-hydroxy-16-methyl-18,20-ethano-13-trans-prostenoate.
 27. 1-9-Oxo-15-hydroxy-17,18-cis-methano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof.
 28. d1-9-Oxo-15-hydroxy 17,18-cis-methano-13-trans-prostenoic acid and the pharmaceutically acceptable cationic salts thereof. 